Abstract

Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR.

Pedigrees of the Six Families Segregating MCORAutosomal-dominant transmission is supported by father-to-son transmission in all six families. Individual numbers in pedigrees FR1 and JP1 are those previously reported. Available DNA can be identified by the presentation of their genotype at the 13q32.1 locus (Del, deletion; +, wild-type allele). Individuals affected with MCOR who were examined by gonioscopy (asterisk) had all iridocorneal angle dysgenesis.

Overview of the 13q32.1 Deletions Identified in MCOROverview of the 13q32.1 locus (chr13: 95,110,000–95,375,000; hg19) with custom tracks showing the delineated deletions presented in this study (horizontal red bars). At the top, the RefSeq Genes Track is included. In addition, ENCODE and conservation tracks are displayed.

Pedigree, GPR180 Genotypes, and Gonioscopic Aspects in Families FR3 and FR1The iris spicules (arrows) consistent with an abnormal development of the iridocorneal angle are seen in individuals harboring the GPR180 c.343C>T (p.Gln115∗) mutation only as well as in individual FR1_V1 affected with microcoria. Abbreviations are as follows: MCOR, microcoria; GD, goniodysgenesis; LCA, Leber congenital amaurosis.